Structural alteration in hypochlorous acid modified antithrombin indicates generation of neo-epitopes

Parvez Ahmad, Irfan Qadir Tantry, Asif Ali, Shahid Ali Siddiqui, Sayeed ur Rehman, Sana Waris, Mohamad Aman Jairajpuri

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Increased tendency of cancer patients to develop venous thromboembolism (VTE) is associated with high rates of mortality. Elevation of procoagulant proteins and down regulation of naturally occurring coagulation inhibitors appears to form the basis of high risk of VTE in malignancy. A reduced level of anticoagulant protein like antithrombin (AT) will influence both coagulation and angiogenesis, as its cleaved and latent conformations show potent antiangiogenic activity. We show a concentration dependent perturbation in the secondary and tertiary structures of AT conformers exposed to hypochlorous acid (HOCl). Modulated under a very narrow concentration range of HOCl, native AT undergoes oligomerization, aggregation and fragmentation based on spectroscopic, SDS and native-PAGE studies. Factor Xa inhibition assay demonstrated a progressive decrease in inhibition activity of AT on modification by HOCl. Bis-ANS result showed that hydrophobic patches were more exposed in the case of HOCl-modified AT when assessed fluorometrically. Dosage of HOCl-modified AT in experimental animals induced high titer antibodies showing more specificity towards modified forms in comparison to unmodified forms. Auto-antibodies isolated from cancer patients also showed enhanced binding with HOCl-modified AT in comparison to native counterpart. Compared to normal AT, structurally and functionally altered conformation of HOCl-modified AT showed increased immunogenic sensitivity. HOCl modified AT can contribute to prothrombotic and angiogenic environment during cancer progression/development.

Original languageEnglish (US)
Article number108332
JournalArchives of Biochemistry and Biophysics
Volume685
DOIs
StatePublished - May 30 2020
Externally publishedYes

Keywords

  • Angiogenesis
  • Antithrombin
  • Cancer
  • Hypochlorous acid
  • Serpins
  • Thrombosis

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology

Fingerprint

Dive into the research topics of 'Structural alteration in hypochlorous acid modified antithrombin indicates generation of neo-epitopes'. Together they form a unique fingerprint.

Cite this